WO2014128538A1 - A process for the preparation of amoxicillin trihydrate - Google Patents

A process for the preparation of amoxicillin trihydrate Download PDF

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Publication number
WO2014128538A1
WO2014128538A1 PCT/IB2013/056612 IB2013056612W WO2014128538A1 WO 2014128538 A1 WO2014128538 A1 WO 2014128538A1 IB 2013056612 W IB2013056612 W IB 2013056612W WO 2014128538 A1 WO2014128538 A1 WO 2014128538A1
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WO
WIPO (PCT)
Prior art keywords
reaction mixture
process according
penicillin
preparation
acid
Prior art date
Application number
PCT/IB2013/056612
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English (en)
French (fr)
Inventor
Rajinder Singh Gujral
Original Assignee
Vardhman Chemtech Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vardhman Chemtech Limited filed Critical Vardhman Chemtech Limited
Publication of WO2014128538A1 publication Critical patent/WO2014128538A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/08—Preparation by forming the ring or condensed ring systems
    • C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P37/00—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin
    • C12P37/04—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin by acylation of the substituent in the 6 position

Definitions

  • the present invention relates to a process for in-situ preparation of Amoxicillin trihydrate from sugarcane juice.
  • Amoxicillin is a moderate-spectrum, bacteriolytic, ⁇ -lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other ⁇ -lactam antibiotics. Amoxicillin is one of the most common antibiotics prescribed for children. Amoxicillin is used to treat many different types of infections caused by bacteria, such as ear infections, bladder infections, pneumonia, gonorrhea, and E. coli or salmonella infection. Amoxicillin is also sometimes used together with another antibiotic called clarithromycin (Biaxin) to treat stomach ulcers caused by Helicobacter pylori infection.
  • clarithromycin Clarithromycin
  • lansoprazole This combination is sometimes used with a stomach acid reducer called lansoprazole (Prevacid). They do not kill bacteria, but they stop bacteria from multiplying by preventing bacteria from forming the walls that surround them. The walls are necessary to protect bacteria from their environment and to keep the contents of the bacterial cell together. Bacteria cannot survive without a cell wall. Amoxicillin is effective against many different bacteria including H. influenzae, N. gonorrhoea, E. coli, Pneumococci, Streptococci, and certain strains of Staphylococci. There are certain methods in the prior art to prepare amoxicillin trihydrate.
  • amoxicillin trihydrate is a multi-step process involving preparations of penicillin G and then 6-aminopenicillanic acid which is subsequently followed by intermediate process steps viz isolation, purification and crystallization of penicillin G and 6-APA.
  • the present invention provides a cost effective, simplified and less laborious in-situ process for the preparation of amoxicillin trihydrate without isolation of the intermediates Penicillin G and 6- aminopenicillanic acid from the reaction sequence.
  • PPAA phenylacetic acid
  • PAA phenylacetic acid
  • the invention provides to the prior art, an in-situ process for the preparation of a beta- lactam antibiotic more specifically it provides a process for the preparation of amoxicillin trihydrate involving in-situ reaction.
  • situ is defined herein as performing two or more reaction sequences without isolating any of the intermediate that is produced during the reaction sequence.
  • the present invention provides an in-situ process for the preparation of Amoxicillin trihydrate from sugarcane juice in which intermediates produced during the reaction are not isolated from the reaction sequence.
  • the process is characterized in the steps comprising: in-situ preparation of a first reaction mixture comprising Penicillin G by fermentation of sugarcane juice with a salt of phenylacetic acid to form a product comprising Penicillin G and thereby purification of the product to form the first reaction mixture which is used for the preparation of second reaction mixture; in-situ enzymatic reaction of the first reaction mixture to prepare a second reaction mixture wherein the preparation is characterized in the steps comprising: reaction of the first reaction mixture with an enzyme to form an intermediate comprising 6-APA and phenylacetic acid (PAA) without isolation of penicillin G from the first reaction mixture.
  • PAA phenylacetic acid
  • penicillin G is prepared separately from sugar from which, 6-aminopenicilaanic acid (6-APA) is prepared separately. These preparations require separate isolation, purification, crystallization steps etc. Then, the 6-APA is reacted with a para-hydroxyphenylglycine derivative to form the amoxicillin trihydrate. But, in the present process, preparation of amoxicillin is carried out directly from the sugarcane juice wherein no intermediate isolation, purification, and crystallization steps are required for intermediates viz penicillin G and 6-APA. These intermediates are produced in-situ i.e. within the system. Thus the process of the present invention comes out to be a cost effective and an efficient process.
  • the invention provides an in-situ process which avoids extra cost of purification, crystallization, equipments.
  • phenylacetic acid is extracted from the system which can be recycled into the system. The recycling allows less consumption of phenylacetic acid and thereby makes the process cost effective.
  • preparation of first reaction mixture comprising Penicillin G is done by fermentation of sugarcane juice with a salt of phenylacetic acid.
  • 2 nd generation spore is inoculated into a seed fermentor having sterilized media at a pH of 6 to 6.1 to form a broth. 10% of the broth is then transferred to the production fermentor.
  • 50% sugarcane juice and 17% metallic salt of phenylacetic acid is added into the production fermentor along with 20% ammonia solution to maintain the pH in range of 6.4 to 6.55 to obtain a product.
  • the product is then, allowed to go through the purification steps for the production of the first reaction mixture comprising Penicillin G.
  • the salt of the phenylacetic acid used is the metallic salt and the metal of the metallic salt is selected from the group comprising of sodium, potassium, magnesium, and aluminum.
  • the purification of the product produced after fermentation is done by ultra-filtration and nano filtration. The ultra filtration is done to remove the unwanted mycelium and microorganisms, whereas nano-filtration is done to concentrate the purified product to form the first reaction mixture comprising penicillin G.
  • the ultra filtration is done twice followed by nano filtration to purify and concentrate the product produced after the fermentation step.
  • the enzyme used is selected from the group consisting of Penicillin G Acylase or Penicillin Amidase.
  • the enzymatic reaction of the first reaction mixture takes place at a pH of 6.8 to 8.5 to form an intermediate comprising 6-APA and PAA.
  • An alkali solution is added to the first reaction mixture along with the enzyme to maintain the pH in range of 6.8 to 8.5.
  • the alkali is selected from the group comprising of sodium bicarbonate, ammonium carbonate, ammonia solution or any other alkali.
  • the intermediate comprising 6- APA and PAA is allowed to settle and is filtered. The filtrate is then washed with de-mineralized water and is cooled at a temperature of 0-30°C.
  • the alkali added is 10% ammonia solution.
  • the acidic solution is added with the organic solvent till the pH of the solution reaches in range of 1 to 3.5 and is selected from the group consisting of HC1, H 2 SO 4 , Acetic Acid and any other low pH acid.
  • HC1 is added with the organic solvent to maintain the pH in range of 1 to 3.5.
  • the organic solvent is selected from the group consisting of toluene, butyl acetate, methylene chloride, methyl isobutyl ketone, ethyl acetate and any other water immiscible solvent.
  • the second reaction mixture is reacted with para- hydroxyphenylglycine (PHPG) derivative in presence of the enzyme to form amoxicillin trihydrate.
  • PHPG para- hydroxyphenylglycine
  • water is added to the second reaction mixture and the pH of the solution is maintained in range of 7.2-7.5 by the addition of 10-12% ammonia, at a temperature of 10-15°C.
  • a first lot of PHPG derivative is added along with the enzyme at a pH of 6.25-6.4 to form a solution of amoxicillin trihydrate.
  • the pH is set by the addition of ammonia solution.
  • the conversion of second reaction mixture to amoxicillin trihydrate is checked after each hour.
  • a second lot of PHPG derivative is added at the same pH and conversion is checked again.
  • a third lot of PHPG derivative is added and the reaction is carried out till the conversion reaches more than 95%.
  • isolation of amoxicillin trihydrate is done by filtering out the amoxicillin trihydrate layer from the enzyme and dissolving the filtrate in aqueous HC1 at a temperature of 23-25°C to remove the traces of the enzyme.
  • isopropyl alcohol is added to the solution at a pH of 5.2-5.3.
  • the pH is set by adding ammonia solution.
  • amoxicillin trihydrate solution is filtered, washed with Isopropyl alcohol, and dried to get amoxicillin trihydrate salt.
  • the para-hydroxyphenylglycine derivative that reacts with the second reaction mixture is an ester or an amide.
  • the process for the preparation of Amoxicillin and its pharmaceutical acceptable salts involves optional recycling of third reaction mixture comprising phenylacetic acid to the fermentation step.
  • the recycling helps in less consumption of phenylacetic acid and better production of Penicillin G which in turns helps producing more 6-APA.
  • the process for the preparation of Amoxicillin and its pharmaceutical acceptable salts is an in-situ process.
  • the process requires no isolation of Penicillin G from the first reaction mixture and 6-APA from the second reaction mixture during the reaction sequence at any stage. Due to this, the process is very useful on commercial scales. It incurs less capital costs since the cost of equipments / machinery used otherwise for purification, crystallization, etc of the intermediates is completely eliminated.
  • the process for the preparation of the amoxicillin salt is quite efficient and cost effective. Also, it proves to generate significant feasibility for the industrial scale production of amoxicillin and pharmaceutical salt there without involving separate preparation of intermediates produced during the reaction sequence. Further, the process of invention results in saving a lot water during the process as opposed to the processes in the prior art that require lot of water in-between. In fact, lowering of water consumption starts with Cane Juice as no water is added to make Sugar solution in Pencillin G. The water in the process can be recycled, thus no special effluent treatment plant are required after every step. Also, there is no need of producing and crystallizing the Sugar during the process as Penicillin G is directly produced from sugarcane juice which helps in saving lot of power.
  • the process for preparation of amoxicillin as described in various embodiments of the present invention is achieved by in-situ preparations of intermediates viz Penicillin G and 6- APA, conferring high purity without the loss of the intermediates during isolation, purification and crystallization procedure.
  • the process of the invention eliminates the requirement of lot of chemicals required to isolate Sugar, Pencillin G, 6-APA as the process of the invention is in-situ, thus making the process cost-effective.
  • the industrial applicability of the process is also enhanced significantly since it can be easily set up at an industrial scale without the use of complex purification methods or equipments, which thereby increase the efficiency and substantially reduce the cost of industrial production. Further, the above discussed advantages of the invention make the process green; thereby help the environment in a great deal.
  • the same process can be used to prepare ampicillin by replacing PHPG ester/amide to phenylglycine ester/amide.
  • Ampicillin comes under same class as that of amoxicillin. In terms of spectrum and level of activity, amoxicillin is roughly treated as the successor of ampicillin.
  • the present invention also provides an in-situ process for the preparation of ampicillin by reacting the second reacting mixture with a phenylglycine derivative in presence of the enzyme.
  • the concentration of the product was made to 31 mg/ml to form the first reaction mixture.
  • 50gm equivalent of first reaction mixture comprising Penicillin G was taken for reaction.
  • Penicillin acylase enzyme was added.
  • the pH was maintained at around 8 by the addition of 10% ammonia solution.
  • the solution was allowed to settle for 5 min and then filtered.
  • the filtrate (Enzyme) was then washed with 90ml de-mineralized water.
  • the temperature of the resulting solution was then cooled to 4-5°C and 170ml of toluene was added in presence of 30% HC1 at a pH in range of 1-1.4 to form an intermediate comprising 6-aminopenicillanic acid (6-APA) and phenylacetic acid (PAA).
  • the intermediate obtained was stirred for 5 min to form an organic layer and an aqueous layer.
  • the organic layer comprising PAA was separated to form a third reaction mixture and recycled into the system whereas the aqueous layer was filtered and wash with 10ml de- mineralized water to form the second reaction mixture.
  • 50gm equivalent of 6-APA (second reaction mixture) was charged at a temperature of 10-15°C and a pH of 7.2-7.5.
  • the pH was maintained by adding 40-45ml of 10-12% ammonia solution. Then, 37.5 gm of para- hydro xyphenylglycine (PHPG) ester dissolved in 100ml of water was added to it. After that, 85- 88gm of penicillin G acylase enzyme was added to it to start the reaction at a pH of 6.25-6.4. The pH was maintained by the addition of 20-25ml of 10-12% ammonia solution. Then, second lot of PHPG ester (18.75gm) in 50ml of water was added to it at the pH of 6.25-6.4 and conversion of 6-APA to amoxicillin trihydrate was checked.
  • PHPG para- hydro xyphenylglycine
  • the pH was set by adding the ammonia solution. Solution was stirred for 1.5 hrs and then filtered at a temperature of 0- 5°C. The amoxicillin trihydrate solution was washed with 100ml of water followed by 50ml of Isopropyl alcohol, and then dried in TD to obtain 83-86gm of amoxicillin trihydrate salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/IB2013/056612 2013-02-22 2013-08-13 A process for the preparation of amoxicillin trihydrate WO2014128538A1 (en)

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IN518DE2013 2013-02-22
IN518/DEL/2013 2013-02-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106497989A (zh) * 2016-11-04 2017-03-15 内蒙古常盛制药有限公司 一种由青霉素钾制备阿莫西林和苯乙酸的方法
CN111978334A (zh) * 2020-08-26 2020-11-24 山东鲁抗医药股份有限公司 一种注射用青霉素菌素盐的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023622A1 (en) * 1996-11-27 1998-06-04 Biochemie Gesellschaft Mbh Purification of fermented clavulanic acid
US20050020685A1 (en) * 2003-06-12 2005-01-27 Skonezny Paul M. Process for recovery of 6-aminopenicillanic acid from an aqueous discharge stream

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023622A1 (en) * 1996-11-27 1998-06-04 Biochemie Gesellschaft Mbh Purification of fermented clavulanic acid
US20050020685A1 (en) * 2003-06-12 2005-01-27 Skonezny Paul M. Process for recovery of 6-aminopenicillanic acid from an aqueous discharge stream

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106497989A (zh) * 2016-11-04 2017-03-15 内蒙古常盛制药有限公司 一种由青霉素钾制备阿莫西林和苯乙酸的方法
CN106497989B (zh) * 2016-11-04 2021-05-04 内蒙古常盛制药有限公司 一种由青霉素钾制备阿莫西林和苯乙酸的方法
CN111978334A (zh) * 2020-08-26 2020-11-24 山东鲁抗医药股份有限公司 一种注射用青霉素菌素盐的制备方法

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